Toll-like receptors (TLRs) are a family of evolutionally conserved pattern recognition receptors (PRRs) expressed by a variety of cell types, particularly those of the innate immune system such as dendritic cells and monocytes. The innate immune system can recognize pathogen-associated molecular patterns (PAMP) via these TLRs expressed on the cell surface of certain types of immune cells. Recognition of foreign pathogens activates the production of cytokines and up-regulation of co-stimulatory molecules on phagocytes. This leads to the modulation of T cell and B cell behaviour (D. J Connolly and L. A J O'Neill, Current Opinion in Pharmacology 2012, 12:510-518).
Toll-like receptor 7 (TLR7) is a member of this receptor class that is found predominantly in the endosomal compartment of plasmacytoid dendritic cells (pDCs), which are the primary source of interferon-α (IFN-α). The receptor is also expressed at significant levels in B cells. The native ligand for TLR7 is single-stranded RNA, particularly of viral origin. Following the binding of ssRNA to TLR7, the receptor in its dimer form is believed to undergo a structural change leading to subsequent recruitment of adaptor proteins, including MyD88, to the cytoplasmic domain and initiation of the receptor signalling cascade. This alternation results in the activation of cytoplasmic transcription factors, including IRF-7 and NF-κB, that undergo translocation to the nucleus and initiate transcription of various genes, e.g., IFN-α and other antiviral cytokine genes. The altered responsiveness of pDCs might contribute to the reduced innate immune responses during chronic viral infections. Agonist-induced activation of TLR7 might therefore represent a novel approach for the treatment of chronic viral infections (P. A. Roethle et al, J. Med. Chem. 2013, 56, 7324-7333).
Agonists of TLR7 mediate antiviral activity against a variety of viruses due to the production of endogenous interferons and other antiviral cytokines, and by induction of an antiviral immune response. Pegylated IFN-α (PEG-IFN-α) is currently used to treat chronic HBV and is an alternative to potentially life-long treatment with antiviral nucleos(t)ide analogues. In a subset of chronic HBV patients, PEG-IFN-α therapy can induce sustained immunologic control of the virus following a finite duration of therapy. However, the percentage of HBV patients that achieve seroconversion with interferon therapy is low (up to 27% for HBeAg-positive patients) and the treatment is typically poorly tolerated. Furthermore, functional cure (defined as HBsAg loss and seroconversion) is also very infrequent with both PEG-IFN-α and nucleos(t)ide treatment. Given these limitations, there is an urgent need for improved therapeutic options to treat and induce a functional cure for chronic HBV. Treatment with an oral, small-molecule TLR7 agonist is a promising approach that has the potential to provide greater efficacy and tolerability (T. Asselah et al, Clin Liver Dis 2007, 11, 839-849).
A number of identified TLR7 agonists have demonstrated anti-viral properties. For example, the TLR7 agonist imiquimod (ALDARA™) was approved by the U.S. FDA as a topical agent for the treatment of skin lesions caused by certain strains of the human papillomavirus. The TLR7/8 agonist resiquimod (R-848) is being evaluated as a topical agent for the treatment of human genital herpes. 852A, a TLR7 agonist, has shown promise in Phase I trials in cancer patients. This compound has also completed a Phase II trial for the treatment of chemotherapy-refractory metastatic melanoma. Another compound, ANA773 is an oral pro-drug TLR7 agonist, developed for the treatment of patients with chronic hepatitis C virus (HCV) infection and cancer (A. X. Xiang et al, Nucleosides, Nucleotides, and Nucleic Acids, 26:635-640, 2007). GS-9620 is an orally available TLR7 agonist. A phase Ib study demonstrated that treatment with GS-9620 was safe, well tolerated and resulted in significant dose-dependent ISG15 mRNA induction in patients with chronic hepatitis B (E. J. Gane et al, Annu Meet Am Assoc Study Liver Dis (November 1-5, Washington, D.C.) 2013, Abst 946). Therefore there are high unmet clinical needs for developing high potent and safe TLR7 agonists as new HBV treatment to offer more therapeutic solutions or replace existing partly effective treatment.